Identification, structure modification, and characterization of potential small-molecule SGK3 inhibitors with novel scaffolds

Abstract

The serum and glucocorticoid-regulated kinase (SGK) family has been implicated in the regulation of many cellular processes downstream of the PI3K pathway. It plays a crucial role in PI3K-mediated tumorigenesis, making it a potential therapeutic target for cancer. SGK family consists of three isoforms (SGK1, SGK2, and SGK3), which have high sequence homology in the kinase domain and similar substrate specificity with the AKT family. In order to identify novel compounds capable of inhibiting SGK3 activity, a high-throughput screening campaign against 50,400 small molecules was conducted using a fluorescence-based kinase assay that has a Z' factor above 0.5. It identified 15 hits (including nitrogen-containing aromatic, flavone, hydrazone, and naphthalene derivatives) with IC values in the low micromolar to sub-micromolar range. Four compounds with a similar scaffold (i.e., a hydrazone core) were selected for structural modification and 18 derivatives were synthesized. Molecular modeling was then used to investigate the structure-activity relationship (SAR) and potential protein-ligand interactions. As a result, a series of SGK inhibitors that are active against both SGK1 and SGK3 were developed and important functional groups that control their inhibitory activity identified.

Design and Characterization of SGK3-PROTAC1, an Isoform Specific SGK3 Kinase PROTAC Degrader

“…13−15 Due to the high homology of their SGK catalytic domains, it has not been possible to elaborate inhibitors that display isoform specificity. 16 These compounds could have less toxicity for treating cancer resistance than inhibitors targeting all isoforms.…”

“…These data support the notion of targeting SGK3 as a therapeutic strategy for counteracting resistance to PI3K/Akt inhibition in cancer treatment. A number of ATP competitive inhibitors that target all SGK isoforms with similar affinity have been reported. − Due to the high homology of their SGK catalytic domains, it has not been possible to elaborate inhibitors that display isoform specificity . These compounds could have less toxicity for treating cancer resistance than inhibitors targeting all isoforms.…”

Identification and Kinetic Characterization of Serum- and Glucocorticoid-Regulated Kinase Inhibitors Using a Fluorescence Polarization–Based Assay

“…The IC 50 values determined in this study are comparable to reported values. 28,29 To further validate the FP assay, the selective SGK inhibitor GSK650394 was chosen as a reference compound, which revealed IC 50 values of 0.033, 0.093, and 5.0 µM for SGK1, SGK2, and SGK3, respectively ( Suppl. Fig.…”

PROteolysis TArgetting Chimeras (PROTACs) Strategy Applied to Kinases: Recent Advances

“…[ 114 ] Thus, the inhibition of SGK3 could constitute a relevant therapeutic target in cancer treatment but, due to the high homology of the SGK ATP domain, it has not been possible to produce until now specific ATP competitive inhibitors that only targeting one isoform of the SGK family. [ 115 ] In this context, the conversion into PROTACs of SGK inhibitors seems to be a reasonable solution to obtain selective compounds that only target one SGK isoform due to the potential increasing selectivity property of PROTAC compounds.…”